This proposal outlines a series of detailed experiments directed toward establishment of a functional lac repressor switch system for control of gene expression within transgenic mice. The system will allow controlled tissue specific regulation from optimally designed lac repressor and lac operator chimeric gene constructions. An additional level of control is provided through the novel application of lac inducers. The availability of transgenic mouse strains containing gene control sequences capable of efficient operation in several tissues of the animal, will assist in the development of human disease models. This transgenic system will also permit dissection of complex developmental pathways through tissue ablation approaches, analysis of the effects of coordinated oncogene expression on tumor promotion and progression, improvements in current short-term mutagenicity testing, and understanding of complex autoimmune diseases. These modifications of the lac regulatory system will act synergistically with the large number of well characterized eukaroytic promoters for establishing controlled gene regulation in transgenic animals.